Separation of erbB2 (red) from its ligand, heregulin (green), limits receptor signaling in airway cells.


Agrowth factor hides from its receptor in a different membrane domain, as demonstrated by Paola Vermeer, Michael Welsh (University of Iowa, Iowa City, IA), and colleagues. The separation normally prevents receptor activation, but can be overcome rapidly when activation is necessary.

The sneaky receptor is erbB2, whose activation by the ligand heregulin stimulates cellular migration and proliferation. Although both erbB2 and heregulin are expressed in airway epithelial cells, the slow division rate of these cells suggests that erbB receptors are not signaling. The Iowa group now shows that erbB2 is inactive because it is separated from its ligand by tight junctions. Whereas heregulin was found in the apical membrane of the epithelial cells, erbB2 resided on the basolateral surface.

The spatial barrier offers a quick fix for damaged epithelia. “The instant any insult occurs,” says Vermeer, “the system is already set up to repair damage without relying on transcription or translation.” As predicted, a wound stimulus activated erbB2 rapidly (within one minute following injury). Blocking either erbB2 or heregulin delayed subsequent wound repair.

On the down side, pathological loss of the physical separation may cause problems in diseases such as asthma, in which tight junctions are not so tight. “When you have loose junctions, you may be chronically stimulating receptors,” says Vermeer. Indeed, asthma patients often have thickened epithelial tissue. The group is now testing whether erbB2 activation accounts for this remodeling. ▪


Vermeer, P., et al.